Morbi mortalidad por infecciones en pacientes con leucemia linfoblástica aguda: recaida en inducción / Infection associated morbidity and mortality in children with relapsed acute limphoblastic leukemia during induction therapy

Los pacientes con Leucemia Linfoblástica Aguda (LLA) recaída reciben quimioterapia (QMT) intensa que produce neutropenia severa y prolongada que condiciona mayor frecuencia de infecciones. Con el fin de evaluar las características clínicas de las infecciones en estos pacientes con neutrepenia y fiebre (NF) luego de la QMT de inducción se realizó un análisis retrospectivo de estos episodios de NF. La QMT de inducción incluyó 10 días de prednisona 100 mg/m2 VO y altas dosis de QMT de 6 días de duración. Recibieron esta QMT 98 pacientes en el período comprendido entre septiembre de 1994 y Diciembre de 2002. De los 96 pacientes evaluables el 73 eran varones y la edad media fue de 110.5 meses. E 28 eran mayores de 12 años. El 64 tenían catéter implantable. el 77 eran eutróficos y el 21 obesos. Presentaron NF 86 pacientes (90). El 29 tuvo sepsis. Todos los episodios de NF cumplieron criterios de alto riesgo. La media de días de internación fue 19.5. El 19 de los niños requirió en Unidad de Cuidados Intensivos (UCI). Recibieron asistencia respiratoria mecánica (ARM) el 16 de los niños. El 52 de los niños tuvo bacteriemia, donde prevalecieron los cocos Gram positivos (29) seguido de bacilos Gram negativos (22). Ochenta y cinco por ciento de los episodios presentaron foco clínico de infección y prevalecieron el foco pulmonar (33.3) y la mucositis oral (32.3). Fallecieron 9 pacientes (9.4). Todas las muertes fueron debidas a sepsis no controlada. La edad mayor a 12 años fue la única variable estadísticamente significtiva relacionada con la mortalidad (OR 6.3, IC 951.4-27.3; p<0.01). La presencia de foco perianal, enteral y el infiltrado pulmonar se asociaron con la presencia de sepsis. Los pacientes con NF luego de la inducción de LLA recaída tienen alta tasa de mortalidad relacionada con la infección, perticularmente la sepsis. En este grupo de pacientes es necesario extremar los cuidados posteriores a la QMT.

Model studies for evaluating the acute neurobehavioral effects of complex hydrocarbon solvents I. Validation of methods with ethanol.

As a preliminary step to evaluating the acute neurobehavioral effects of hydrocarbon solvents and to establish a working model for extrapolating animal test data to humans, joint neurobehavioral/toxicokinetic studies were conducted which involved administering ethanol to rats and volunteers. The specific objectives of the present studies were to evaluate the acute central nervous system (CNS) effects of ethanol in rats and humans and to assess relationships between internal levels of exposure and behavioral effects. A more general objective was to validate a battery of neurobehavioral tests that could be used to carry out comparative studies in both species. Accordingly, a range of tests including standardized observational measures, spontaneous motor activity assessments and learned visual discrimination performance was utilized in rat studies to evaluate acute CNS effects. Groups of rats were given ethanol at levels of approximately 0.5, 1.0 or 2.0g/kg, with blood level measurements to verify internal doses. In a volunteer study, 12 healthy male subjects were given 0.65g/kg ethanol, a level approximating the limit for motor vehicle operation in The Netherlands, and neurobehavioral effects were measured prior to and 1 and 3h after ethanol administration, with a computerized neurobehavioral test battery. Blood and air measurements were made to quantify internal doses. Results of the behavioral tests in rats provided evidence of ethanol-induced changes in neuromuscular, sensori-motor, and activity domains. There were also significant changes in visual discrimination, particularly in the areas of general measures of responding and psychomotor speed. In humans there were small but statistically significant effects on learning and memory, psychomotor skills and attention. However, the effects were subtle and not all parameters within given domains were affected. These studies demonstrated a qualitative similarity in response between rats and humans.

Methoxyflurane enhances allyl alcohol hepatotoxicity in rats. Possible involvement of increased acrolein formation.

The effect of methoxyflurane anesthesia on allyl alcohol-induced hepatotoxicity and the metabolism of allyl alcohol was studied in male rats. Hepatotoxicity was assessed by the measurement of serum alanine aminotransferase activity and histopathological examination. Allyl alcohol-induced hepatotoxicity was enhanced when allyl alcohol (32 mg/kg) was administered 4 hr before or up to 8 days after a single 10-min exposure to methoxyflurane vapors. The possibility that methoxyflurane increases alcohol dehydrogenase-dependent oxidation of allyl alcohol to acrolein, the proposed toxic metabolite, was evaluated by measuring the rate of acrolein formation in the presence of allyl alcohol and liver cytosol. The effect of methoxyflurane on alcohol dehydrogenase activity in liver cytosol was also assessed by measuring the rate of NAD+ utilization in the presence of ethyl alcohol or allyl alcohol. Alcohol dehydrogenase activity and rate of acrolein formation were elevated in methoxyflurane-pretreated rats. The results suggest that a modest increase in alcohol dehydrogenase activity and rate of acrolein formation markedly enhances allyl alcohol-induced hepatotoxicity.

Bleomycin-induced DNA-strand damage in isolated male germ cells.

DNA strand damage in isolated male germ cells (MGC) was evaluated after in vitro exposure to bleomycin (BLM), a known genotoxin. The alkaline elution technique was used to determine DNA-strand breaks. Concentration-dependent strand damage was established following exposure to bleomycin for 1 h at 37 degrees C. Exposure at 0 degrees C resulted in an increase in the frequency of strand breaks as compared to those observed at 37 degrees C. Pretreatment of cells with deferoxamine (DM), an iron-selective chelating agent, abolished the DNA damage induced by bleomycin. Isolated male germ cells responded in a predictable and reproducible manner thus supporting their use in mechanistic studies of genotoxicity.

Accumulation of a commercial polychlorinated biphenyl mixture (Aroclor 1016) in adult rhesus monkeys and their nursing infants.

Female rhesus monkeys (24) were divided into 3 groups and fed diets calculated to contain 1.0, 0.25 or 0 parts per million (ppm) of a commercial mixture of polychlorinated biphenyls (PCBs), Aroclor 1016. The animals consumed a calculated total of 18.1 +/- 3.1, 4.5 +/- 0.6 and 0 mg Aroclor 1016/kg of body weight over the 87 +/- 9 week experimental period. All animals were bred, conceived and experienced uncomplicated pregnancies. The birth weights of the infants born to females receiving the 1.0 ppm PCB diets were significantly less than those of the control infants. There was a positive relationship between the levels of Aroclor 1016 in the tissues and the dose administered in the diets. Aroclor 1016 content of infant tissues was consistent with maternal adipose tissue PCB levels. The content of Aroclor 1016 in the milk fat of the animals more closely approximated that in the individual's adipose tissue than in the serum. At weaning, the mesenteric fat of the experimental infants contained concentrations of Aroclor 1016 which were 4-7 times that found in the mothers. Analyses of the tissues and fluids of the experimental animals demonstrated accumulation of PCB isomerides. The number of isomerides present and the ratio of those detected differed between adult and infants as well as between milk and serum. After weaning, the pattern of Aroclor 1016 isomerides present in the infants' adipose was similar to that observed at weaning although the concentrations had decreased.

Locomotor hyperactivity in PCB-exposed rhesus monkeys.

Various aspects of locomotor activity were measured, using a crossed photobeam cage, in young rhesus monkeys (M. mulatta) whose mothers had been fed low levels of polychlorinated biphenyls (PCBs, Aroclor 1248) both before and during gestation and nursing. In Exp. 1, a group of young monkeys whose mothers had been fed 2.5 ppm PCBs (the 2.5 ppm concurrent-exposure group) was compared with the control group of Exp. 1 at 6 (Exp la) and 12 (Exp lb) mon of age. In Exp. lla, a group of young monkeys born from the same 2.5 ppm mothers after they had been off their 2.5 ppm PCB diets for periods ranging from 0.5 to 1.5 yr (i.e., the 2.5 ppm post-exposure group) was compared with the control group of Exp. II at 12 mon of age. In Exp. IIb, two groups of young monkeys from groups of mothers fed 0.5 and 1.0 ppm PCBs three times per week (concurrent-exposure) were compared at 12 mon of age with the control group of Exp. II. In the 12-mon tests the mean data and variability of the two control groups were very similar, both in their mean locomotor activity levels in early sessions and in activity at about half that level in later sessions, suggesting between-session adaptation over the course of the experiment. In contrast, both the concurrent and the post-exposure 2.5 ppm groups showed between-session patterns which began at control activity levels but which rose to levels at least three times those of the controls by the final sessions. In the tests conducted at 12 mon of age, locomotor activity for 15 min periods within each daily session were within measurement error of being stable for all groups except the 0.5 and 1.0 ppm groups of Exp. llb. The former exhibited increasing activity throughout each session, a pattern which persisted across all 24 sessions run. On the other hand, the 1.0 ppm group showed within-session decrements which became less pronounced as the experiment continued. This latter pattern was the only one shown by any group which was consistent with the concept of "reactivity". Overall, all of the PCB-treated groups were more active than their controls with no quantitative difference related to PCB dosage. Dose-effect differences appeared in the form of qualitatively different activity patterns between the groups, for which no quantitative description appeared obvious.

Effects of climate-controlled housing on reproductive potential of rhesus monkeys.

The reproductive adaptability of newly acquired female feral rhesus monkeys was evaluated by comparison of their menstrual records and progesterone levels with those of females in captivity for 3 1/2 years. Housing of the animals under conditions that simulated conditions of the breeding season in the wild resulted in a rapid adjustment with minimal periods of amenorrhoea or anovulation. Both groups of monkeys were similar with respect to menstruation and menstrual cycle length and progesterone levels.

Residual effects of polychlorinated biphenyls on adult nonhuman primates and their offspring.

After 18 mo of consuming a diet containing 2.5 and 5.0 ppm PCB (Aroclor 1248), during which they and their offspring experienced marked alterations in physical status, female rhesus monkeys were placed on a control diet for 1 yr. During this year there was a decided improvement in their general body health and reproductive capabilities. Infants born to these animals were small at birth and during their postnatal life developed signs of PCB intoxication similar to those observed in their siblings born during the period of PCB exposure. These data indicate that the residual effects of low-level ingestion of PCBs by nonhuman primates persist for over 1 yr after discontinuation of exposure. There are also indications that the fetal and neonatal monkeys born to PCB-exposed mothers are more severely affected for a longer period than are the adult female monkeys.

Responses of nonhuman primates to a polybrominated biphenyl mixture.

In a series of experiments, rhesus monkeys have been given in their diets 0.3, 1.5, and 25 ppm of a commercial polybrominated biphenyl (PBB) (as FireMaster FF-1). The seven adult female monkeys receiving 0.3 ppm PBB have been on the treatment regime for 15 months and have consumed over 22 mg of PBB. During the initial 6 months of exposure, they lost weight and 2 of the animals develop sterile abscesses. At 6 months, 4 of the 7 animals had flattened and lengthened serum progesterone peaks. This change was correlated with an increase in length of their menstrual cycles. After 6 months of PBB exposure, the animals were bred. Two of the 7 animals showed excessive and prolonged implantation bleeding. Two abortions and 5 live births were recorded. All of the experimental infants were smaller than the controls at birth. The animals receiving a diet containing 1.5 ppm PBB for 36 weeks (total intake 70 mg) have shown a moderate weight loss and decrease in serum cholesterol. Similar changes have also been recorded in the group given the 25 ppm PBB diet for 14 weeks (approximately 500 mg total intake). In addition, these animals have also developed a hyperplastic gastritis.

The effects of transplacental and mammary movement of PCBs on infant rhesus monkeys.

Sixteen adult female rhesus monkeys were fed diets containing 2,5 and 5.0 ppm PCB (Aroclor 1248) for approx. 1.5 years. 6 of the 8 animals on 5 ppm PCB and 8 of the 8 animals on 2.5 ppm PCB conceived when bred after 6 months' exposure to PCB. Only 1 live infant was born to the animals of the 5.0 ppm group and 5 infants to the animals in the 2.5 ppm PCB group. All of the infants had PCBs in their tissues at birth. Thereafter, there was a rapid increase in the PCB levels of the infants' tissues. This increase was attributed to consumption of PCB-containing milk from their mothers. Within 2 months following birth the infants had facial acne and edema, swelling of the eyelids, loss of facial hair including eyelashes, and hyperpigmentation of the skin. Three of the 6 infants had expired within 8 months following birth due to PCB intoxication. The three survivors were weaned and subsequently showed marked improvement in their physical state.